Identifying pathogenic B cells in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects approximately 1% of the population. It is a life-limiting disease which primarily targets the joints, causing pain, swelling, and stiffness. However, additional organ systems can also be affected, demonstrated by an increased risk of cardiovascular disease and pulmonary fibrosis. There is currently no cure for RA, so treatments focus on the management of symptoms, the slowing of disease progression and the prevention of irreversible joint damage and functional disability.

The pathogenesis of RA is complex and not yet fully understood, but many immune cells are known to have a role in the development of disease. The role of B cells in RA pathogenesis has been demonstrated by the efficacy of B cell depletion therapies (i.e. Rituximab, an anti-CD20 biological therapy that ablates all CD20+ B cells). As well as being the source of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), the most prevalent autoantibodies in RA, B cells also contribute to joint inflammation via antibody-independent actions, such as pro-inflammatory cytokine production. Whilst B cell depletion therapy is effective at treating RA, it is expensive and the ablation of all CD20+ B cells increases the risk of infection, limiting its use. Identifying the B cell subset to target would create a more specific therapeutic target and potentially a cure if only pathogenic B cells could be permanently depleted.

This project aims to identify the pathogenic B cells and a biomarker of treatment response in RA by conducting a comprehensive analysis of B cells in highly treatment resistant RA patients. To do this we will assess the frequency of B cell subtypes (by flow cytometry) and their gene expression before and after B cell depletion therapy. Incorporating clinical data will create a multi-dimensional dataset and allow us to better understand the B cell subtypes driving disease. By comparing the data of those who respond to treatment with those who don't we hope to identify a biomarker of response and illuminate the key pathogenic players that drive inflammation.